New amino ether derivatives of orthothymotic esters

ABSTRACT

Amino ethers of the general formula:   IN WHICH R is a lower alkyl radical having 1-4 carbon atoms, R2 and R3 which may be the same or different are hydrogen or a lower alkyl radical or, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally containing another heteroatom, n is an integer from 1 to 4, R4 is hydrogen or a lower alkyl radical, the various R4&#39;&#39;s not being necessarily identical when n is higher than 1, X and Y are hydrogen or nitro, and their pharmaceutically acceptable salts. They are useful, particularly, as diuretic, respiratory analeptic, cranial and peripheral vasodilatator, antiarrhythmic and antispasmodic drugs.

United States Patent 1191 Castaigne 1451 Sept. 16, 1975 AMINO ETHER DERIVATIVES OF ORTHOTHYMOTIC ESTERS [75] Inventor: Albert Rene Castaigne, Toulouse,

France [73] Assignee: Centre dEtudes pour llndustrie Pharmaceutique, Toulouse, France 22 Filed: July 5,1973

211 App]. No.: 376,906

[52] U.S. Cl.. 260/471 R; 260/2472 B; 260/293.82; 424/248; 424/267; 424/309 [51] Int. Cl. C07C 101/42 [58] Field of Search 260/471 R [56] References Cited Primary Examiner-Robert Gerstl Asxistant Exuminer-L. A. Thaxton Attorney, Agent, or FirmYoung & Thompson [57] ABSTRACT Amino ethers of the general formula:

CH -x 00- on 2 4 Y I O-(CHR )n- 3 a R H O CH in which R is a lower alkyl radical having l-4 carbon atoms, R and R which may be the same or different are hydrogen or a lower alkyl radical or, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally containing another heteroatom, n is an integer from 1 to 4, R* is hydrogen or a lower alkyl radical, the various R 's not being necessarily identical when n is higher than 1, X and Y are hydrogen or nitro, and their pharmaceutically acceptable salts.

They are useful, particularly, as diuretic, respiratory analeptic, cranial and peripheral vasodilatator, antiarrhythmic and antispasmodic drugs.

8 Claims, No Drawings NEW AMINO ETHER DERIVATIVES ()F ORTHOTHYMOTIC ESTERS 0.011 X I c Y (CR N (I) I n \RB a H C CH in which R is a lower alkyl radical having 1-4 carbon atoms, R and R, which may be the same or different, are hydrogen or a lower alkyl radical having l6 carbon atoms or, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally containing another heteroatom, n is an integer from 1 to 4, R considered individually in each --(CHR) radical is hydrogen or a lower alkyl radical having 1-6 carbon atoms, X and Y are hydrogen or nitro, and their pharmaceutically acceptable salts.

It is apparent from the preceding definition that the various symbols R are not necessarily the same when n is greater than 1.

Among the acid addition salts, there may be mentioned the salts formed with inorganic acids (hydrochloric, sulfuric, phosphoric acids) or organic acids (oxalic, citric, fumaric acids, and the like).

The invention includes also within its scope a process for the preparation of said derivatives, comprising reacting an ortho-thymotic acid, having the formula:

3 X i C O OH I OH P3 H C C H COR in which R is OR, and then reacting derivative (ll) with an aminoalkyl halide of the formula: J

in which R R, R and n have the above defined meanings and Z is halogen, and, if desired, salifying the resulting derivative of the formula (I);

The first step of the reaction uses orthothymotic acid or the 3-and/or 4-substituted derivatives of this acid when X and/or Y are other than hydrogen. Said substituted derivatives are readily obtained by nitration of ortho-thymotic acid, the nitro group or groups introduced being readily convertible to the amino and then to the halogeno group by a conventional reaction sequence.

As a modification, when it is desired to obtain derivatives of the formula (I) in which X- and/or Y are other than hydrogen, ortho-thymotic acid (X Y H) may nevertheless be used in the first step and the desired substituents X and/or Y may then be introduced at a subsequent step by. the above mentioned reaction sequence, particularly after esterification of orthothymotic acid. I

Said esterification is advantageously effected with an alkyl sulfate. The reaction is preferably conducted within boiling acetone in the presence of sodium acid carbonate.

The reaction of the resulting derivative (ll) with the aminoalkyl halide is effected by using the latter as the salt with the corresponding acid ZH. The reaction is preferably conducted within boiling acetone in the presence of potassium carbonate.

The resulting compounds'of the formula (I) are isolated either as the free bases or as acid addition salts, or also as quaternary ammonium derivatives.

The following non limiting examples are given to illustrate the preparation of the compounds of this invention.

Examples A and B relate to the preparation of ,esters (ll) used as raw materials insubsequent examples.

EXAMPLE A Synthesis of methyl orthothymotate To a two-necked flask provided with a mechanical stirrer and an ascending cooler with a calcium chloride tube overhead, are added 48.55 g (0.25 mole) orthothymotic acid, 35.28 g (0.28 mole) methyl sulfate, 25.2 g (0.30 mole) sodium acid carbonate and 200 ml anhydrous acetone.

The mixture is boiled during 15 hours, with continuous stirring.

After cooling, the solution is filtered and the filter is washed with acetone. The filtrate and washing liquors are evaporated in vacuo. The residue is dissolved in ether, washed with a saturated aqueous sodium acid carbonate solution andwith water until neutral.

The ether phase is then separated, dried over sodium sulfate and evaporated. The resulting oily residue is then distilled in vacuo and the fraction distilling at 88-89C under 0.5 mm mercury is collected. Yield: 78%.

EXAMPLE B Synthesis of ethyl orthothymotate This ester is obtained as its methyl homolog (Example A) by mixing at first 48.55 g (0.25 mole) orthothymotic acid, 45.17 g (0.28 mole) ethyl sulfate and 25.2 g sodium acid carbonate in 200 ml anhydrous acetone.

The fraction distilling at 8889C under 0.5 mm Hg is collected. Yield: 78%.

EXAMPLE 1 Synthesis of ethyl Z-(B-dimethylaminoethoxy )-3-isopropyl- 6-methyl-benzoate (Compound (I), R OC H and 68.75 g anhydrous potassium carbonate (0.5 mole) in 300 ml anhydrous acetone. I

Refluxing is maintained during 60 hours, with continuous stirring. After cooling, the solution is filtered, the residue is washed with acetone and the acetone liquors are evaporated to dryness. The residue is dissolved in 100 ml of N HCl, washed with ether and then made al- -kaline with 2N sodium hydroxide, after which it is 'ex tracted with etheri This latter ether phase is washed with water substantially saturated with sodium chloride, dried over anhydrous sodium sulfate and then concentrated in vacuo.

The resulting oil is distilled in vacuo and the fraction distilling between 1 18 and 122C under 0.10 mm Hg is collected. Yield: 65%.

EXAMPLE 2 Synthesis of methyl 2-(a-methyl-B-dimethylaminoethoxy)- 3-isopropyl-6-methyI-benzoate (Compound (I); R OCH Under the same conditions as in the preceding example, 20.26 g (0.0974 mole) methyl ortho-thymotate, 20.1 g 2-chloro-l-dimethylamino-propane hydrochloride (0.127 mole) and 59.4 g anhydrous potassium car bonate (0.43 mole) are mixed in 200 ml acetone.

On distillation, the fractions distilling between 118 and 121C under 0.1 mm Hg are collected. Yield: 54%.

EXAMPLE 3 In a three-necked flask provided with a dropping funnel, a cooler and a magnetic stirrer, are dissolved 5 g (0.024 mole) methyl ortho-thymotate in 19 ml glacial acetic acid. The mixture is cooled externally by means of an ice bath. A mixture of nitric acid (2.7 ml; d 1.38) in glacial acetic acid (19 ml) is added thereto, dropwise, and the reaction mixture is then left aside during 2 hours at room temperature, after which it is poured over crushed ice.

After filtration, washing with water, drying and recrystallization from petroleum ether, there are obtained 44 g (Yield 72%) methyl 5-nitro-orthothymotate havinga melting point (Koefler block) of 7072C.

b. Synthesis of methyl Z-(B-dimethylaminoethoxy)-3-isopropyl- 6-methyl-5-nitro-benzoate.

To a three-necked flask provided with a cooler (provided overhead with a calcium chloride trap) and with a magnetic stirrer are added 20 g (0.079 mole) methyl 5-nitro-orthothymotate, 38.7 g (0.28 mole) anhydrous potassium carbonate, 1413 g 2-chloro-1-N- dimethylamino-ethane hydrochloride (0.099 mole) and 200 ml acetone. The mixture is refluxed during 36 hours and is then filtered, the precipitate is washed with acetone and the filtrate is evaporated. Hydrochloric acid'( 100 ml) is added to the'residue and the impurities areextracted with ether.

The aqueous phase is then made alkaline and extracted with ether. The ether extracts are washed with water, dried over anhydrous sodium sulfate, filtered and evaporated, to give 8.7 g of an oil. (Yield: 34%).

This oil is converted to the hydrochloride which is recrystallized from ethyl acetate-ethanol.

For indicative purposes: other derivatives of the formula (I) were prepared. The following Table summarizes the characteristics of the chief derivatives ob tained.

The results of toxicological and pharmacological tests reported below demonstrate the useful activities of the derivatives of this invention, particularly their diuretic, respiratory analeptic, cranial and peripheral vasodilator, antiarrhythmic and antispasmodic activities.

Thus, this invention relates also to a therapeutic composition, having in particular diuretic, respiratory analeptic, cranial and peripheral vasodilatator, antiarrhythmic and antispasmodic actions, comprising, as active ingredient, a derivative of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

I. TOXICOLOGICAL INVESTIGATION The low toxicity and good tolerance of the derivatives of this invention are apparent from the data resulting from said investigation.

For indicative purposes, the LD 50/24 hrs, determined according to the method by Miller and Tainter in mice, for the intravenous route and per kg of body weight is 39 mg for derivative 1, 38 mg for derivative 2, 32 mg for derivative 3, 30 mg for derivative 4, 78 mg. for derivative 6, 38 mg for derivative 8 and 35 mg for derivative 10.

, R. Derivative (CHR),,--N Y R Y B.p.C ().l mm Hg Yield Salt; m.p., C

rm :i f Y 1 v I 1 N 6 0011,. H H 119 47,7 Hydrochloride 163--' 165, 2 CH2CH2-N (CH5): OC2H5 H ll8 48 Hydrochloride 122 179 l80 3 CH CH N (C H OCHg; H H 133 45- Hydrochloride V 134 l06- l08 4 (H2CH2N (3H,, 1, (3 H H H 120 56 oxalate 5 cH, cH 2-N mm H H 24- Oxalate 6 CH2--CH2N y 0 ()CH,, H H 58 Hydrochloride 7 CH CH N 1 o, 0cm, H H '33 U Hydrochloride l 1*. Y o 0 8 CH Cl-l=i1--CH -N CH,, OCH H" H 118 34' Hydrochloride 121 95- 105 9 CH :i)C 2' (CH3): 1 2 5 H i H I Hydrochloride.

' l36- l38 10 cH, cH, c1-i, N cH,,), oci'i H; H 119 1 Hydrocrlloaride a 120 -1|1- 1 11 (H2 cH,-N cH OCH, No H 208 I 34 Hydrochloride By the oral route, the LD 50/24 hrs is above 0 mg The results of this investigation showthat the derivafor all the derivatives. i tives of this invention ossess diuretic, res irator ana- P P y leptic cranial arid peripheral vasodilatatory antiar- 3.0 i s u," a u 0. I PHARMACOL [CAL INVESTIGATION .rhythmic and antispasmodic activities and that they a. diuretic-actioru i may, therefore, constitute the active ingredient of a on oral administrafibnhtb Wistarrats"; therapeutic composition valuable for use in human and 100 mg/kg, the compounds of this invention induce a Veterinary medlcme' The F." m be advanta' marked increase of diuresis. This action is particularly 35 formulate? for therapeunf: m the form of noteworthy in the case of derivatives 1 2 and 8 an in ectable solution or of suppositories. It may also be formulated, for oral administration, as tablets, coated b. respiratory analeptic action tablets, capsules, syrups and drops. Each unit dose may The respiratory analeptic effect of derivatives 1, 3 advantageously contain from 10 m to 200 mg active and 10 is apparent from said investigation. On intrave- 40 mgredlem and the dally do sage reglme may vary nous administration to rabbits at a dosage of 30 mg/kg, 10 to 1000 mg deperfdmg the of they produce a marked durable increase in the tration and on the severity of the condition treated. quency of the respiratory motions Non limitingexamplesof: pharmaceutic formulations of the composition of this invention are given below. c. cranial and peripheral vasodilatator action The experimentation was conducted in rabbits: the derivatives of this invention were slowly injected by the intravenous route at a dosage of 10 mg/kg. The rheo- EXAMPLE 4' TABLETS graphic study shows an increased amplitude of the rem no 2 0.100 g cording, corresponding to an increase of the blood rate Corn starch 0.010 g of flow and reflecting a cranial and peripheral vasodilarignesium g 8 C tation. Said action was apparent in the case of deriva- Polyvinyl pyrmlidone @005 g tives 3, 4, 6, and 8. Glucose 0.010 g EXAMPLE 5. COATED TABLETS d. anti-arrhythmic action Derivative 4 0-050 2 Lactose 0.010 g On slow intravenous administration to rabbits, at a Core 2 Magnesium stearate 0.005 g Corn starch 0.0l0g dosage of 5 mg/kg, derivatives 2 and 3 of this invention Glucose (mm g protect completely the test animals against barium 2 Gum arabic 0.010 g Shellac 0.005 g chloride induced arrhythmia. Coming Talc 0.002 g i v White wax 0.001 g e. antispasmo 1c action Camauba wax truce Alcohol 0002 g This investigation, carried out on the isolated organ, Sugar (1.5. for i coated v i ta et shows that derivatives Z and 3 of this invention acting EXAMPLE 6' CAPSULES on the ileum of guinea-pig or the duodenum of rat sub- W Derivmive no (00 g mitted to the action of a contracture inducing agent Magnesium Slearate g EXAMPLE 7. SYRUP barium chloride, acetylcholine or histamine) produce mfive no I 1 g a substantial decrease of the contractions. Flavoured exipiem, rm )0 ml -Continued' EXAMPLE 8. lNJECl'ABLE SOLUTION Derivative .no. 6 g 0.020 g lsotonic solvent, q.s. for 3 ml EXAMPLE 9. SUPPOSITORIES Derivative no. 3 0.050 g Semi-synthetic glycerides. q.s. for l suppository The composition of this invention may be efficiently administrated for therapeutic purposes.

in which R is selected from the lower alkyl radicals having 1-4 carbon atoms; R and R are individually selected from hydrogen and the lower alkyl radicals having l-6 carbon atoms; n is an integer from 1 to 4; R

5 considered individually in each radical (CHR)-- is By inducing substantial liquid depletions, by stimulat ing the vital control centers of the respiratory function,

by regulating the rhythm of the heart muscle and by normalizing its stimulability, by permitting improved cranial and peripheral oxygenation and by increasing the blood rate of flow, it constitutes a choice medication for the treatment of cardiovascular conditions.

In addition, in view of its antispasmodic action, it lifts the spams of the unstriated muscle fibres and alleviates the urogenital, intestinal or biliary pains.

Having now described my invention what I claim as new and desire to secure by Letters Patent is:

l. A compound selected from the amino ether derivatives of ortho-thymotic estersof the formula:

selected from hydrogen and the lower alkyl radicals having 1-6 carbon atoms; and X and Y are each selected from hydrogen and nitro; and their pharmaceutically'acceptable acid addition salts.

2. Methyl 2-(B-dimethylaminoethoxy)-3-isopropyl-6- methylbenzoate and its hydrochloride.

3. Ethyl 2-(B-dimethylarninoethoxy}3 isopropyl-6- methylbenzoate and its hydrochloride.

4. Methyl 2-( fl-diethylaminoethoity )-3-isopropyl-6- methylbenzoate and its hydrochloride.

5. Methyl 2-(a-methyl-,B-dimethylaminoethoxy)-3- isopropyl--methyl-benzoate and its hydrochloride.

6. Ethyl I 2-(a-methyl-B-dimethylaminoethoxy)-3- isopropyl-6-methyl benzoate and its hydrochloride.

7. Methyl i2-( y-dirnethylaminopropoxy)-3-isopropylo-methyl-benzoate and its hydrochloride.

8. Methyl 2-( fi-dimethylai'ninoethoxy)-3-isopropyl-6- methylj-nitro benzoate and its hydrochloride. 

1. A COMPOUND SELECTED FROM THE AMINO ETHER DERIVATIVES OF ORTHO-THYMOTIC ESTERS OF THE FORMULA:
 2. Methyl 2-( Beta -dimethylaminoethoxy)-3-isopropyl-6-methylbenzoate and its hydrochloride.
 3. Ethyl 2-( Beta -dimethylaminoethoxy)-3-isopropyl-6-methylbenzoate and its hydrochloride.
 4. Methyl 2-( Beta -diethylaminoethoxy)-3-isopropyl-6-methylbenzoate and its hydrochloride.
 5. Methyl 2-( Alpha -methyl- Beta -dimethylaminoethoxy)-3-isopropyl-6-methyl-benzoate and its hydrochloride.
 6. Ethyl 2-( Alpha -methyl- Beta -dimethylaminoethoxy)-3-isopropyl-6-methyl benzoate and its hydrochloride.
 7. Methyl 2-( gamma -dimethylaminopropoxy)-3-isopropyl-6-methyl-benzoate and its hydrochloride.
 8. Methyl 2-( Beta -dimethylaminoethoxy)-3-isopropyl-6-methyl-5-nitro benzoate and its hydrochloride. 